Adenoviruses are associated with acute respiratory, gastrointestinal, and ocular infections. While several different Ad types can cause eye infections (viral pink eye), only subgroup D Ad types (Ad37, Ad19 and Ad8) are associated with a particularly severe ocular disease known as epidemic keratoconjunctivitis (EKC). Until recently, knowledge of subgroup D host cell tropism was quite limited. We discovered that the relatively short and inflexible Ad37 fiber protein restricts virus interactions with CAR, the cell receptor used by most other Ad types. To overcome this limitation, Ad37 uses a distinct cell receptor, CD46 (also known as Membrane Cofactor Protein) to bind to host cells. In this proposal, we will investigate the precise molecular interactions involved in Ad37 binding to CD46 using biochemical and molecular genetic approaches. Complementary studies will analyze the three dimensional structure of Ad-CD46 complexes at moderate to high resolution using cryoelectron microscopy or X-ray diffraction. CD46 has been usurped by diverse microbial pathogens and thus, this receptor may serve important functions beyond host cell recognition. In this regard, our recent studies showed that Ad37 downregulates expression of interleukin-12 (IL-12). This key inflammatory cytokine links the innate and adaptive immune response and therefore may play a crucial role in viral clearance. In further studies, we will examine the mechanisms involved in Ad-mediated cytokine regulation. We will also analyze whether CD46 expression in relevant cell and animal models enhances Ad37 infection in vitro and in vivo. These studies should increase our understanding of Ad tropism and ocular pathogenesis. They may also provide insights for the development of novel antiviral agents as well as improved gene delivery vectors.